Cone pathophysiology and activated hypoxic response

Marijana Samardzija

Human vision depends largely on cones, which are responsible for high acuity and color vision. Degeneration of cones (e.g. in age-related macular degeneration (AMD)) leads to severe visual impairment and blindness. Previously we have shown that activation of HIF1 in rods leads to retinal degeneration and may be involved in the development of AMD. We have also shown that Hif1a can be safely inactivated in normal cone photoreceptors without negative effects for retinal function or morphology. In this project, we aim to study the impact of HIF1 activation in cones, with specific emphasis on comparing the consequence of activation in healthy versus already degenerative cones.

We aim to address following questions: i) How do healthy cones respond to Hif1a activation? ii) Do cones respond in a similar way as rod photoreceptors to the stabilisation of HIF1, i.e. are the cones similarly vulnerable to HIF1 stabilization as rods? iii) What are the effects of an artificiallyactivated hypoxic response on the ongoing degenerative process in cones? 

To stabilize HIF1A, we use a mouse model with cone-specific Cre recombinase deleting Vhl in cones of healthy mouse retinas and in cones of mouse models with cone degeneration. To ensure that the observed effects are HIF1-specific, mouse lines with additional Hif1a deletion are generated and used as controls.

Hypoxia plays an important role in development of age-related neurological diseases. The photoreceptors in the eyes of elderly people are probably burdened by a hypoxic environment, which is at least partially a result of restricted oxygen supply related to ageing. Uncovering molecules/signaling pathways governed by the hypoxic response in photoreceptors should lead to the identification of potential neuroprotective factors with ultimate goal to develop treatment strategies to prevent cone loss.